This proposal is to continue our studies of brain aging in rhesus macaques that have been calorically restricted since 1989 or 1994. We will investigate processes and mechanisms that may explain why caloric restriction (CR) exerts a salutary effect on the brain. The key hypothesis is that a metabolic shift occurs due to CR. In this study we will employ a powerful array of investigative tools: MRI to examine longitudinal change in brain morphology, FDG PET to examine glucose metabolic function, detailed cognitive and behavioral testing to examine executive, memory and fine motor dexterity, and on the animals that have died due to natural causes throughout the course of the long-running study, we will examine the brain in fine detail for neuropathologic features and for key indicators of metabolic changes.
Aim 1 of this study examines longitudinal change on brain MRI including volumetric changes, and iron deposition changes. In addition we will employ newer scan sequences to obtain greater characterization of white and gray matter.
Aim 2 will examine cognitive and motor function using an already existing touch screen response system.
Aim 3 examines fine-grained neurohistopathology features including histological characterization of beta amyloid, tau, p-tau, synaptic density, and reactive astrocytes (GFAP).
Aim 4 examines the central hypothesis that CR induces an upregulated state of energy metabolism in the brain assessed in vivo with PET FDG and in situ with assays of key metabolic regulators PGC-1a, SIRT1, mTOR, and AMPK. Finally Aim 5 provides an integrative Aim examining associative convergence among the various markers in the study that would lead us to conclude that CR retards the aging process in multiple domains. The significance of this project is quite high since body weight is a modifiable risk factor for disease. In order for CR or CR mimetics to be applied in humans it is critical to understand the effect of CR on the brain in a primate model. In this project we will attain a comprehensive and completely novel set of data on the long-term (18-23 years) effects of CR on the brain and behavior. The powerful combination of the metabolic and structural imaging, cognitive assessment and in-situ brain assays obtained in this multidisciplinary and translational project will lead to better understanding of the mechanisms by which CR affects the brain.

Public Health Relevance

The elderly are the fastest growing segment of the U.S. population and this will only increase as baby boomers began turning 65 in 2011. Thus, functional, cognitive and physical declines associated with brain aging and age-related neuro-diseases will also rise, as will health care burden and costs required to treat these conditions. CR and/or CR-mimetics may be a viable means to prolong healthy brain function if it can be shown to be effective in a primates model of aging (which is the goal of this project), and ultimately in humans.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AG043125-03
Application #
8704847
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wise, Bradley C
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Madison
State
WI
Country
United States
Zip Code
53715
Sridharan, Aadhavi; Bendlin, Barbara B; Gallagher, Catherine L et al. (2014) Effect of age and calorie restriction on corpus callosal integrity in rhesus macaques: a fiber tractography study. Neurosci Lett 569:38-42
Zakszewski, Elizabeth; Adluru, Nagesh; Tromp, Do P M et al. (2014) A diffusion-tensor-based white matter atlas for rhesus macaques. PLoS One 9:e107398
Willette, A A; Coe, C L; Birdsill, A C et al. (2013) Interleukin-8 and interleukin-10, brain volume and microstructure, and the influence of calorie restriction in old rhesus macaques. Age (Dordr) 35:2215-27
Sridharan, Aadhavi; Pehar, Mariana; Salamat, M Shahriar et al. (2013) Calorie restriction attenuates astrogliosis but not amyloid plaque load in aged rhesus macaques: a preliminary quantitative imaging study. Brain Res 1508:1-8